Intravascular delivery of methylprednisolone

ABSTRACT

The present invention provides improved devices and methods for minimizing and/or inhibiting restenosis and hyperplasia after intravascular intervention. In particular, the present invention provides luminal prostheses which allow for programmed and controlled methylprednisolone delivery with increased efficacy to selected locations within a patient&#39;s vasculature to inhibit restenosis. An intraluminal delivery prosthesis may comprise an expansible structure and means on or within the structure for releasing methylprednisolone into the body lumen to inhibit smooth muscle cell proliferation.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of Provisional Application No.60/258,024, filed Dec. 22, 2000, under 37 C.F.R. §1.78(a)(3), the fulldisclosure of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to medical devices and methods.More particularly, the present invention provides luminal prostheses,such as vascular stents and grafts, which allow for controlled substancedelivery for inhibiting restenosis in a blood vessel following balloonangioplasty or other interventional treatments.

A number of percutaneous intravascular procedures have been developedfor treating stenotic atherosclerotic regions of a patient's vasculatureto restore adequate blood flow. The most successful of these treatmentsis percutaneous transluminal angioplasty (PTA). In PTA, a catheter,having an expansible distal end usually in the form of an inflatableballoon, is positioned in the blood vessel at the stenotic site. Theexpansible end is expanded to dilate the vessel to restore adequateblood flow beyond the diseased region. Other procedures for openingstenotic regions include directional arthrectomy, rotationalarthrectomy, laser angioplasty, stenting, and the like. While theseprocedures have gained wide acceptance (either alone or in combination,particularly PTA in combination with stenting), they continue to sufferfrom significant disadvantages. A particularly common disadvantage withPTA and other known procedures for opening stenotic regions is thefrequent occurrence of restenosis.

Restenosis refers to the re-narrowing of an artery after an initiallysuccessful angioplasty. Restenosis afflicts approximately up to 50% ofall angioplasty patients and is the result of injury to the blood vesselwall during the lumen opening angioplasty procedure. In some patients,the injury initiates a repair response that is characterized by smoothmuscle cell proliferation referred to as “hyperplasia” in the regiontraumatized by the angioplasty. This proliferation of smooth musclecells re-narrows the lumen that was opened by the angioplasty within afew weeks to a few months, thereby necessitating a repeat PTA or otherprocedure to alleviate the restenosis.

A number of strategies have been proposed to treat hyperplasia andreduce restenosis. Previously proposed strategies include prolongedballoon inflation during angioplasty, treatment of the blood vessel witha heated balloon, treatment of the blood vessel with radiation followingangioplasty, stenting of the region, and other procedures. While theseproposals have enjoyed varying levels of success, no one of theseprocedures is proven to be entirely successful in completely avoidingall occurrences of restenosis and hyperplasia.

As an alternative or adjunctive to the above mentioned therapies, theadministration of therapeutic agents following PTA for the inhibition ofrestenosis has also been proposed. Therapeutic treatments usually entailpushing or releasing a drug through a catheter or from a stent. Ofparticular interest herein, stents may incorporate a biodegradable ornondegradable matrix to provide programmed or controlled release oftherapeutic agents within a blood vessel. Biodegradable or bioerodiblematrix materials employed for controlled release of drugs may includepoly-l-lactic acid/poly-e-caprolactone copolymer, polyanhydrides,polyorthoesters, polycaprolactone, poly vinly acetate,polyhydroxybutyrate/polyhyroxyvalerate copolymer, polyglycolic acid,polyactic/polyglycolic acid copolymers and other aliphatic polyesters,among a wide variety of polymeric substrates employed for this purpose.

While holding great promise, the delivery of therapeutic agents for theinhibition of restenosis has not been entirely successful. Inparticular, the release of drugs from stents has often beencharacterized by inconsistent and/or ineffective results becausetherapeutic agents are often released before they are needed, i.e.,before hyperplasia and endothelialization begin. Drug delivery beforeany cellular or endothelial formation may also pose serious dangers,especially when dealing with the delivery of certain toxic agents.Furthermore, a rapid initial release of drugs causes delayedendothelialization and/or enlargement of the vessel wall, as asubstantial number of cells are killed with increased drug loading. Theuse of drug release matrices can ameliorate the rapid release problemsbut do not provide programmed time-delay to impact restenosis at theonset of hyperplasia.

For these reasons, it would be desirable to provide improved devices andmethods for reducing and/or inhibiting restenosis and hyperplasiafollowing angioplasty and other interventional treatments. Inparticular, it would be desirable to provide improved devices andmethods, utilizing luminal prostheses, such as vascular stents andgrafts, which provide programmed and controlled substance delivery withincreased efficacy to inhibit restenosis. It would further be desirableto provide such devices and methods which would reduce and/or furthereliminate drug washout and potentially provide minimal to no hindranceto endothelialization of the vessel wall. At least some of theseobjectives will be met by the devices and methods of the presentinvention described hereinafter.

2. Description of the Background Art

Method and apparatus for releasing active substances from implantableand other devices are described in U.S. Pat. Nos. 6,096,070; 5,824,049;5,624,411; 5,609,629; 5,569,463; 5,447,724; 5,464,650; and 5,283,257.The use of stents for drug delivery within the vasculature are describedin PCT Publication No. WO 01/01957 and U.S. Pat. Nos. 6,099,561;6,071,305; 6,063,101; 5,997,468; 5,980,551; 5,980,566; 5,972,027;5,968,092; 5,951,586; 5,893,840; 5,891,108; 5,851,231; 5,843,172;5,837,008; 5,769,883; 5,735,811; 5,700,286; 5,679,400; 5,649,977;5,637,113; 5,591,227; 5,551,954; 5,545,208; 5,500,013; 5,464,450;5,419,760; 5,411,550; 5,342,348; 5,286,254; and 5,163,952. Biodegradablematerials are described in U.S. Pat. Nos. 6,051,276; 5,879,808;5,876,452; 5,656,297; 5,543,158; 5,484,584; 5,176,907; 4,894,231;4,897,268; 4,883,666; 4,832,686; and 3,976,071. The use ofhydrocylosiloxane as a rate limiting barrier is described in U.S. Pat.No. 5,463,010. Methods for coating of stents is described in U.S. Pat.No. 5,356,433. Coatings to enhance biocompatibility of implantabledevices are described in U.S. Pat. Nos. 5,463,010; 5,112,457; and5,067,491.

The disclosure of this application is related to the disclosures of thefollowing applications being filed on the same day: Ser. Nos.09/783,253; 09/782,927; and 09/783,254.

The full disclosures of each of the above references are incorporatedherein by reference.

SUMMARY OF THE INVENTION

The present invention provides improved devices and methods forinhibiting restenosis and hyperplasia after intravascular intervention.In particular, the present invention provides luminal prostheses whichallow for programmed and controlled methylprednisolone delivery withincreased efficiency and/or efficacy to selected locations within apatient's vasculature to inhibit restenosis. Moreover, the presentinvention provides minimal to no hindrance to endothelialization of thevessel wall.

The term “intravascular intervention” includes a variety of correctiveprocedures that may be performed to at least partially resolve astenotic, restenotic, or thrombotic condition in a blood vessel, usuallyan artery, such as a coronary artery. Usually, the corrective procedurewill comprise balloon angioplasty. The corrective procedure could alsocomprise directional atherectomy, rotational atherectomy, laserangioplasty, stenting, or the like, where the lumen of the treated bloodvessel is enlarged to at least partially alleviate a stenotic conditionwhich existed prior to the treatment.

Methylprednisolone acts by inhibiting inosine monophosphatedehydrogenase and guanosine monophosphate synthetase enzymes in the denovo purine biosynthesis pathway. This may cause the cells to accumulatein the G1-S phase of the cell cycle and thus result in inhibition of DNAsynthesis and cell proliferation (hyperplasia). In the presentapplication, the term “methylprednisolone” is used to refer tomethylprednisolone itself and to pro-drugs and/or pharmaceuticallyderivatives thereof (precursor substances that are converted into anactive form of methylprednisolone in the body).

In a first aspect of the present invention, a vascular prosthesiscomprises an expansible structure which is implantable within astructure lumen and means on or within the structure for releasingmethylprednisolone into the body lumen to minimize and/or inhibit smoothmuscle cell proliferation. Methylprednisolone release will typically beat rates in a range from 5 μg/day to 200 μg/day, preferably in a rangefrom 10 μg/day to 60 μg/day. The total amount of methylprednisolonereleased will typically be in a range from 100 μg to 10 mg, preferablyin a range from 300 μg to 2 mg, more preferably in a range from 500 μgto 1.5 mg. Thus, the present invention also improves the efficiency andefficacy of methylprednisolone delivery by releasing methylprednisoloneat a rate and/or time which inhibits smooth muscle cell proliferation.

The expansible structure may be in the form of a stent, whichadditionally maintains luminal patency, or may be in the form of agraft, which additionally protects or enhances the strength of a luminalwall. The expansible structure may be radially expansible and/orself-expanding and is preferably suitable for luminal placement in abody lumen. The body lumen may be any blood vessel in the patient'svasculature, including veins, arteries, aorta, and particularlyincluding coronary and peripheral arteries, as well as previouslyimplanted grafts, shunts, fistulas, and the like. It will be appreciatedthat the present invention may also be applied to other body lumens,such as the biliary duct, which are subject to excessive neoplastic cellgrowth, as well as to many internal corporeal tissue organs, such asorgans, nerves, glands, ducts, and the like. An exemplary stent for usein the present invention is described in co-pending application Ser. No.09/565,560, the full disclosure of which is incorporated herein byreference.

In a first embodiment, the means for releasing methylprednisolonecomprises a matrix formed over at least a portion of the structure. Thematrix may be composed of a material which is degradable, partiallydegradable, nondegradable polymer, synthetic, or natural material.Methylprednisolone may be disposed within the matrix or adjacent to thematrix in a pattern that provides the desired release rate.Alternatively, methylprednisolone may be disposed on or within theexpansible structure adjacent to the matrix to provide the desiredrelease rate. Suitable biodegradable or bioerodible matrix materialsinclude polyanhydrides, polyorthoesters, polycaprolactone, poly vinlyacetate, polyhydroxybutyrate-polyhyroxyvalerate, polyglycolic acid,polyactic/polyglycolic acid copolymers and other aliphatic polyesters,among a wide variety of polymeric substrates employed for this purpose.A preferred biodegradable matrix material of the present invention is acopolymer of poly-l-lactic acid and poly-e-caprolactone. Suitablenondegradable matrix materials include polyurethane, polyethylene imine,cellulose acetate butyrate, ethylene vinyl alcohol copolymer, or thelike.

The polymer matrix may degrade by bulk degradation, in which the matrixdegrades throughout, or preferably by surface degradation, in which asurface of the matrix degrades over time while maintaining bulkintegrity. Hydrophobic matrices are preferred as they tend to releasemethylprednisolone at the desired release rate. Alternatively, anondegradable matrix may release the substance by diffusion.

In some instances, the matrix may comprise multiple adjacent layers ofsame or different matrix material, wherein at least one layer containsmethylprednisolone and another layer contains methylprednisolone, atleast one substance other than methylprednisolone, or no substance. Forexample, methylprednisolone disposed within a top degradable layer ofthe matrix is released as the top matrix layer degrades and a secondsubstance disposed within an adjacent nondegradable matrix layer isreleased primarily by diffusion. In some instances, multiple substancesmay be disposed within a single matrix layer.

The at least one substance other than methylprednisolone may comprise animmunosuppressive agent selected from the group consisting of rapamycin,mycophenolic acid, riboflavin, tiazofurin, mizoribine, FK 506, zafurin,and methotrexate. Such immunosuppressive substances, likemethylprednisolone, may be useful in the present invention to inhibitsmooth muscle cell proliferation. Alternatively, the at least onesubstance other than methylprednisolone may comprise at least one agentselected from the group consisting of anti-platelet agent (e.g., plavax,ticlid), anti-thrombotic agent (e.g., heparin, heparin derivatives), andIIb/IIa agent (e.g., integrilin, reopro). The agent may also be aprodrug of any of the above listed agents.

Additionally, a rate limiting barrier may be formed adjacent to thestructure and/or the matrix. Such rate limiting barriers may benonerodible or nondegradable, such as silicone, polytetrafluorethylene(PTFE), paralene, and parylast, and control the flow rate of releasepassing through the rate limiting barrier. In such a case,methylprednisolone may be released by diffusion through the ratelimiting barrier. Furthermore, a biocompatible or blood compatiblelayer, such as polyethylene glycol (PEG), may be formed over the matrixor rate limiting barrier to make the delivery prosthesis morebiocompatible.

In another embodiment, the means for releasing the substance maycomprise a rate limiting barrier formed over at least a portion of thestructure. Methylprednisolone may be disposed within the barrier oradjacent to the barrier. The rate limiting barrier may have a sufficientthickness so as to provide the desired release rate ofmethylprednisolone. Rate limiting barriers will typically have a totalthickness in a range from 0.01 micron to 100 microns, preferably in arange from 0.1 micron to 10 microns, to provide methylprednisolonerelease at the desired release rate. The rate limiting barrier istypically nonerodible such as silicone, PTFE, parylast, polyurethane,parylene, or a combination thereof and methylprednisolone releasethrough such rate limiting barriers is usually accomplished bydiffusion. In some instances, the rate limiting barrier may comprisemultiple adjacent layers of same or different barrier material, whereinat least one layer contains methylprednisolone and another layercontains methylprednisolone, at least one substance other thanmethylprednisolone, or no substance. Multiple substances may also becontained within a single barrier layer.

In yet another embodiment, the means for releasing the substancecomprises a reservoir on or within the structure containingmethylprednisolone and a cover over the reservoir. The cover may bedegradable or partially degradable over a preselected time period so asto provide the desired methylprednisolone release rate. The cover maycomprise a polymer matrix, as described above, which containsmethylprednisolone within the reservoir. A rate limiting barrier, suchas silicone, may additionally be formed adjacent to the reservoir and/orthe cover, thus allowing methylprednisolone to be released by diffusionthrough the rate limiting barrier. Alternatively, the cover may be anondegradable matrix or a rate limiting barrier.

Another vascular prosthesis comprises an expansible structure which isimplantable within a body lumen and a rate limiting barrier on thestructure for releasing methylprednisolone into the body lumen toinhibit smooth muscle cell proliferation. The barrier comprises multiplelayers, wherein each layer comprises parylast or paralene and has athickness in a range from 50 nm to 10 microns. At least one layercontains methylprednisolone and another layer containsmethylprednisolone, at least one substance other thanmethylprednisolone, or no substance.

Yet another vascular prosthesis comprises an expansible structure, asource of methylprednisolone on or within the structure, and a source ofat least one other substance in addition to methylprednisolone on orwithin the structure. The methylprednisolone is released from the sourcewhen the expansible structure is implanted in a blood vessel. The atleast one additional substance is released from the source when theexpansible structure is implanted in a blood vessel. Each source maycomprise a matrix, rate limiting membrane, reservoir, or other ratecontrolling means as described herein. The at least one additionalsubstance may be an immunosuppressive substance selected from the groupconsisting of rapamycin, mycophenolic acid, riboflavin, tiazofurin,mizoribine, FK 506, zafurin, and methotrexate. Optionally, the at leastone additional substance may comprise at least one agent selected fromthe group consisting of anti-platelet agent, anti-thrombotic agent, andIIb/IIa agent.

In another aspect of the present invention, methods for inhibitingrestenosis in a blood vessel following recanalization of the bloodvessel are provided. For example, one method may include implanting avascular prosthesis in a blood vessel to prevent reclosure of the bloodvessel. Methylprednisolone is then released into the blood vessel so asto inhibit smooth muscle cell proliferation. The releasing comprisesdelaying substantial release of methylprednisolone for at least one hourfollowing implantation of the prosthesis. The inhibiting release maycomprise slowing release from a reservoir with a material that at leastpartially degrades in a vascular environment over said one hour. In someinstances, release may be slowed with a matrix that at least partiallydegrades in a vascular environment over said one hour. In otherinstances, release may be slowed with a nondegradable matrix or ratelimiting barrier that allows diffusion of methylprednisolone throughsaid nondegradable matrix or barrier after said one hour.Methylprednisolone release will typically be at rates in a range from 5μg/day to 200 μg/day, preferably in a range from 10 μg/day to 60 μg/day.Typically, methylprednisolone is released within a time period of 1 dayto 45 days in a vascular environment, preferably in a time period of 7day to 21 days in a vascular environment.

The prosthesis may be coated with a matrix or barrier by spraying,dipping, deposition, or painting. Such coatings may be non-uniform. Forexample, the coating may be applied to only one side of the prosthesisor the coating may be thicker on one side. Likewise, the prosthesis mayalso incorporate methylprednisolone by coating, spraying, dipping,deposition, chemical bonding, or painting methylprednisolone on all orpartial surfaces of the prosthesis.

Another method for inhibiting restenosis in a blood vessel followingrecanalization of the blood vessel comprises implanting a vascularprosthesis in the blood vessel to prevent reclosure. Methylprednisoloneand at least one other substance in addition to methylprednisolone arereleased when the prosthesis is implanted in the blood vessel. The atleast one additional substance may be an immunosuppressive substanceselected from the group consisting of rapamycin, mycophenolic acid,riboflavin, tiazofurin, mizoribine, FK 506, zafurin, and methotrexate.Preferably, the immunosuppressive substance is mycophenolic acid ormizoribine. Typically, methylprednisolone may be released within a timeperiod of 2 days to 3 months. Optionally, the at least one additionalsubstance may comprise at least one agent selected from the groupconsisting of anti-platelet agent, antithrombotic agent, and IIb/IIIaagent. Release of methylprednisolone and the at least additionalsubstance may be simultaneous or sequential.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 1A are cross-sectional views of a delivery prosthesisimplanted in a body lumen.

FIG. 2 is a digital photograph of an exemplary stent of the deliveryprosthesis prior to expansion.

FIG. 3 is a graphical representation of substance release over apredetermined time period.

FIG. 4 is a partial cross-sectional view of a delivery prosthesis havinga matrix for releasing a substance disposed within the matrix.

FIG. 5 is a partial cross-sectional view of a delivery prosthesis havinga scaffold containing a substance.

FIG. 6 is a partial cross-sectional view of a delivery prosthesis havinga scaffold and a substance disposed on a scaffold surface.

FIG. 7 is a partial cross-sectional view of a delivery prosthesis havingmultiple matrix layers.

FIG. 8 is a partial cross-sectional view of a delivery prosthesis havinga matrix between a rate limiting barrier and a biocompatible layer.

FIG. 9 is a partial cross-sectional view of a delivery prosthesis havinga reservoir type releasing means.

FIG. 10 is a partial cross-sectional view of a delivery prosthesishaving magnetic releasing means.

FIG. 11 is a partial cross-sectional view of a delivery prosthesis withcellular growth.

FIGS. 12A–12C illustrates a method for positioning a delivery prosthesisin a blood vessel in order to deliver a substance therein.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

The present invention provides improved devices and methods forinhibiting restenosis and hyperplasia after intravascular intervention.In particular, the present invention provides luminal prostheses whichallow for programmed and controlled methylprednisolone delivery withincreased efficacy to selected locations within a patient's vasculatureto inhibit restenosis.

FIGS. 1 and 1A illustrate a delivery prosthesis 16 constructed inaccordance with the principles of the present invention. The luminaldelivery prosthesis 16 comprises a scaffold 10 which is implantable in abody lumen 18 and means 20 on the scaffold 10 for releasingmethylprednisolone 22. Methylprednisolone 22 is released over apredetermined time pattern comprising an initial phase whereinmethylprednisolone delivery rate is below a threshold level and asubsequent phase wherein methylprednisolone delivery rate is above athreshold level.

It will be appreciated that the following depictions are forillustration purposes only and does not necessarily reflect the actualshape, size, or distribution of the delivery prosthesis 16. For example,the means or source 20 for releasing methylprednisolone (matrix, ratelimiting barrier, reservoir, and other rate controlling means) may becoupled to a portion, inside, outside, or both sides of the prosthesis.The term “coupled to” includes connected to, attached to, adjacent to,and like configurations. Additionally, methylprednisolone 22 may bedisposed within the means or source for releasing themethylprednisolone, on or within the scaffold, or the methylprednisolonemay alternatively be adhering to the scaffold, bonded to the scaffold,or entrapped within the scaffold. This applies to all depictionshereinafter.

The body lumen 18 may be any blood vessel in the patient's vasculature,including veins, arteries, aorta, and particularly including coronaryand peripheral arteries, as well as previously implanted grafts, shunts,fistulas, and the like. It will be appreciated that the presentinvention may also find use in body lumens 18 other than blood vessels.For example, the present invention may be applied to many internalcorporeal tissue organs, such as organs, nerves, glands, ducts, and thelike.

The scaffold 10 will comprise a stent or graft, which may be partiallyor completely covered by one or more layer of cells. As a stent example,the scaffold 10 will usually comprise at least two radially expansible,usually cylindrical, ring segments. Typically, the scaffold 10 will haveat least four, and often five, six, seven, eight, ten, or more ringsegments. At least some of the ring segments will be adjacent to eachother but others may be separated by other non-ring structures.

By “radially expansible,” it is meant that the segment can be convertedfrom a small diameter configuration to a radially expanded, usuallycylindrical, configuration which is achieved when the scaffold 10 isimplanted at a desired target site. The scaffold 10 may be minimallyresilient, e.g., malleable, thus requiring the application of aninternal force to expand and set it at the target site. Typically, theexpansive force can be provided by a balloon, such as the balloon of anangioplasty catheter for vascular procedures. The scaffold 10 preferablyprovides sigmoidal links between successive unit segments which areparticularly useful to enhance flexibility and crimpability of thestent.

Alternatively, the scaffold 10 can be self-expanding. Suchself-expanding structures are provided by utilizing a resilientmaterial, such as a tempered stainless steel or a superelastic alloysuch as a Nitinol™ alloy, and forming the body segment so that itpossesses its desired, radially-expanded diameter when it isunconstrained, i.e. released from the radially constraining forces of asheath. In order to remain anchored in the body lumen, the scaffold 10will remain partially constrained by the lumen. The self-expandingscaffold 10 can be tracked and delivered in its radially constrainedconfiguration, e.g., by placing the scaffold 10 within a delivery sheathor tube and removing the sheath at the target site.

The dimensions of the scaffold 10 will depend on its intended use.Typically, the scaffold 10 will have a length in a range from about 5 mmto 100 mm, usually being from about 8 mm to 50 mm, for vascularapplications. The small (radially collapsed) diameter of cylindricalscaffold 10 will usually be in a range from about 0.5 mm to 10 mm, moreusually being in a range from 0.8 mm to 8 mm for vascular applications.The expanded diameter will usually be in a range from about 1.0 mm to100 mm, preferably being in a range from about 2.0 mm to 30 mm forvascular applications. The scaffold 10 will have a thickness in a rangefrom 0.025 mm to 2.0 mm, preferably being in a range from 0.05 mm to 0.5mm.

The ring segments may be formed from conventional materials used forbody lumen stents and grafts, typically being formed from malleablemetals, such as 300 series stainless steel, or from resilient metals,such as superelastic and shape memory alloys, e.g., Nitinol™ alloys,spring stainless steels, and the like. It is possible that the bodysegments could be formed from combinations of these metals, orcombinations of these types of metals and other non-metallic materials.Additional structures for the body or unit segments of the presentinvention are illustrated in U.S. Pat. Nos. 5,195,417; 5,102,417; and4,776,337, the full disclosures of which are incorporated herein byreference.

Referring now to FIG. 2, an exemplary stent 10 (which is described inmore detail in co-pending application Ser. No. 09/565,560) for use inthe present invention comprises from 4 to 50 ring segments 12 (withseven being illustrated). Each ring segment 12 is joined to the adjacentring segment by at least one of sigmoidal links 14 (with three beingillustrated). Each ring segment 12 includes a plurality, e.g., sixstrut/hinge units, and two out of each six hinge/strut structures oneach ring segment 12 will be joined by the sigmoidal links 14 to theadjacent ring segment. FIG. 2 shows the stent 10 in a collapsed ornarrow diameter configuration.

Referring now to FIG. 3, a graphical representation ofmethylprednisolone release over a predetermined time period isillustrated. The predetermined time pattern of the present inventionimproves the efficiency of drug delivery by releasing methylprednisoloneat a lower or minimal delivery rate during an initial phase. Once asubsequent phase is reached, the delivery rate of methylprednisolone maybe substantially higher. Thus, time delayed methylprednisolone releasecan be programmed to impact restenosis at the onset of initial cellulardeposition or proliferation (hyperplasia). The present invention canfurther minimize methylprednisolone washout by timing methylprednisolonerelease to occur after at least initial cellularization. Moreover, thepredetermined time pattern may reduce methylprednisolone loading and/ormethylprednisolone concentration as well as potentially provide minimalto no hindrance to endothelialization of the vessel wall due to theminimization of drug washout and the increased efficiency ofmethylprednisolone release.

Methylprednisolone is an antiproliferative antimetabolite which inhibitsinosine monophosphate dehydrogenase and guanosine monophosphatesynthetase enzymes in the de novo purine biosynthesis pathway. This maycause the cells to accumulate in the G1-S phase of the cell cycle andthus result in inhibition of DNA synthesis and cell proliferation(hyperplasia). Another way to administer methylprednisolone is throughthe use of a prodrug (precursor substances that are converted into anactive form in the body). In addition to methylprednisolone, a number ofdrugs which inhibit inosine monophosphate dehydrogenase may be useful inthe present invention to inhibit smooth muscle cell proliferation.Examples of such drugs include rapamycin, mycophenolic acid, riboflavin,tiazofurin, mizoribine, FK 506, zafurin, and methotrexate.

Methylprednisolone delivery may perform a variety of functions,including preventing or minimizing proliferative/restenotic activity,inhibiting thrombus formation, inhibiting platelet activation,preventing vasospasm, or the like. The total amount ofmethylprednisolone released depends in part on the level and amount ofvessel injury, and will typically be in a range from 100 μg to 10 mg,preferably in a range from 300 μg to 2 mg, more preferably in a rangefrom 500 μg to 1.5 mg. The release rate during the initial phase willtypically be from 0 μg/day to 50 μg/day, usually from 5 μg/day to 30μg/day. The methylprednisolone release rate during the subsequent phasewill be much higher, typically being in the range from 5 μg/day to 200μg/day, usually from 10 μg/day to 100 μg/day. Thus, the initial releaserate will typically be from 0% to 99% of the subsequent release rates,usually from 0% to 90%, preferably from 0% to 75%. A mammalian tissueconcentration of the substance at an initial phase will typically bewithin a range from 0 μg/mg of tissue to 100 μg/mg of tissue, preferablyfrom 0 μg/mg of tissue to 10 μg/mg of tissue. A mammalian tissueconcentration of the substance at a subsequent phase will typically bewithin a range from 1 picogram/mg of tissue to 100 μg/mg of tissue,preferably from 1 nanogram/mg of tissue to 10 μg/mg of tissue.

The duration of the initial, subsequent, and any other additional phasesmay vary. Typically, the initial phase will be sufficiently long toallow initial cellularization or endothelialization of at least part ofthe stent, usually being less than 12 weeks, more usually from 1 hour to8 weeks, more preferably from 12 hours to 2 weeks, most preferably from1 day to 1 week. The durations of the subsequent phases may also vary,typically being from 4 hours to 24 weeks, more usually from 1 day to 12weeks, more preferably in a time period of 2 days to 8 weeks in avascular environment, most preferably in a time period of 3 days to 50days in a vascular environment.

In some instances, the release profile of methylprednisolone over apredetermined time may allow for a higher release rate during an initialphase, typically from 40 μg/day to 300 μg/day, usually from 40 μg/day to200 μg/day. In such instances, methylprednisolone release during thesubsequent phase will be much lower, typically being in the range from 1μg/day to 100 μg/day, usually from 10 μg/day to 40 μg/day. The durationof the initial phase period for the higher release rate will be in arange from 1 day to 7 days, with the subsequent phase period for thelower release rate being in a range from 2 days to 45 days. A mammaliantissue concentration of the substance at the initial phase of 1–7 dayswill typically be within a range from 10 nanogram/mg of tissue to 100μg/mg of tissue. A mammalian tissue concentration of the substance atthe subsequent phase of 2–45 days will typically be within a range from0.1 nanogram/mg of tissue to 10 μg/mg of tissue. In other instances, therelease of methylprednisolone may be constant at a rate between 5 μg/dayto 200 μg/day for a duration of time in the range from 1 day to 45 days.A mammalian tissue concentration over this period of 1–45 days willtypically be within a range from 1 nanogram/mg of tissue to 10 μg/mg oftissue.

In one embodiment, the means for releasing methylprednisolone comprisesa matrix or coat 20 formed over at least a portion of the scaffold 10,wherein the matrix 20 is composed of material which undergoesdegradation. As shown in FIG. 4, methylprednisolone 22 may be disposedwithin the matrix 20 in a pattern that provides the desired releaserates. Alternatively, methylprednisolone 22 may be disposed within or onthe scaffold 10 under the matrix 20 to provide the desired releaserates, as illustrated respectively in FIGS. 5 and 6.

It will be appreciated that the scaffold 10 acts as a mechanical supportfor the delivery matrix 20, thus allowing a wide variety of materials tobe utilized as the delivery matrix 20. Suitable biodegradable orbioerodible matrix materials include polyanhydrides, polyorthoesters,polycaprolactone, poly vinly acetate,polyhydroxybutyrate-polyhyroxyvalerate, polyglycolic acid,polyactic/polyglycolic acid copolymers and other aliphatic polyesters,among a wide variety of synthetic or natural polymeric substratesemployed for this purpose.

An example of a biodegradable matrix material of the present inventionis a copolymer of poly-l-lactic acid (having an average molecular weightof about 200,000 daltons) and poly-e-caprolactone (having an averagemolecular weight of about 30,000 daltons). Poly-e-caprolactone (PCL) isa semi crystalline polymer with a melting point in a range from 59° C.to 64° C. and a degradation time of about two years. Thus, poly-l-lacticacid (PLLA) can be combined with PCL to form a matrix that generates thedesired release rates. A preferred ratio of PLLA to PCL is 75:25(PLLA/PCL). As generally described by Rajasubramanian et al. in ASAIOJournal, 40, pp. M584–589 (1994), the full disclosure of which isincorporated herein by reference, a 75:25 PLLA/PCL copolymer blendexhibits sufficient strength and tensile properties to allow for easiercoating of the PLLA/PLA matrix on the scaffold. Additionally, a 75:25PLLA/PCL copolymer matrix allows for controlled drug delivery over apredetermined time period as a lower PCL content makes the copolymerblend less hydrophobic while a higher PLLA content leads to reduced bulkporosity.

The polymer matrix 20 may degrade by bulk degradation, in which thematrix degrades throughout, or preferably by surface degradation, inwhich only a surface of the matrix degrades over time while maintainingbulk integrity. Alternatively, the matrix 20 may be composed of anondegradable material which releases methylprednisolone by diffusion.Suitable nondegradable matrix materials include polyurethane,polyethylene imine, cellulose acetate butyrate, ethylene vinyl alcoholcopolymer, or the like.

Referring now to FIG. 7, the matrix 20 may comprise multiple layers 24and 26, each layer containing methylprednisolone, a different substance,or no substance. As shown, a top layer 24 may contain no substance whilea bottom layer 26 contains methylprednisolone 22. As the top layer 24degrades, the methylprednisolone 22 delivery rate increases.Additionally, the present invention may employ a rate limiting barrier28 formed between the scaffold 10 and the matrix 20, as illustrated inFIG. 8, or may optionally be formed over the matrix 20. Such ratelimiting barriers 28 may be nonerodible and control the flow rate ofrelease by diffusion of the methylprednisolone 22 through the barrier28. Suitable nonerodible rate limiting barriers 28 include silicone,PTFE, parylast, and the like. Furthermore, a layer 30, such aspolyethylene glycol (PEG), and the like, may be formed over the matrix20 to make the delivery prosthesis 16 more biocompatible.

In another embodiment, as illustrated in FIG. 9, the means for releasingmethylprednisolone comprises a reservoir 32 on or within the scaffold 10containing the methylprednisolone 22 and a cover 34 over the reservoir32. The cover 34 is degradable over a preselected time period so thatrelease of methylprednisolone 22 from the reservoir 32 beginssubstantially after the preselected time period. The cover 34, in thisexample, may comprise a polymer matrix, as described above, whichcontains the methylprednisolone 22 within the reservoir 32 so that thematrix 34 is replenished by the methylprednisolone 22 within thereservoir 32. A rate limiting barrier 28, as described with reference toFIG. 8, may additionally be formed between the reservoir 32 and thecover 34, or on top of the cover 34, thus allowing themethylprednisolone to be released by diffusion through the rate limitingbarrier 28.

In operation, methods for methylprednisolone delivery comprise providinga luminal prosthesis incorporating or coupled to the methylprednisolone.The prosthesis is coated with a matrix which undergoes degradation in avascular environment (FIGS. 4–9). The prosthesis is implanted in a bodylumen (FIGS. 12A–12C) so that at least a portion of the matrix degradesover a predetermined time period and substantial methylprednisolonerelease begins after the portion has degraded. Optionally, theprosthesis may be coated with a rate limiting barrier or nondegradablematrix having a sufficient thickness to allow diffusion of themethylprednisolone through the barrier or nondegradable matrix. Theprosthesis is implanted in a body lumen so that substantialmethylprednisolone release from the barrier or nondegradable matrixbegins after a preselected time period. As the proliferative effects ofrestenosis usually occur within a few weeks to a few months, substantialrelease of methylprednisolone will begin within a time period of 4 hoursto 24 weeks in a vascular environment, preferably in a time period of 1day to 12 weeks in a vascular environment, more preferably in a timeperiod of 2 days to 8 weeks in a vascular environment, most preferablyin a time period of 3 days to 50 days in a vascular environment.

Methylprednisolone may be incorporated in a reservoir in a scaffold, asshown in FIG. 9, or on a scaffold. In this configuration, the reservoiris covered by the matrix so that methylprednisolone release beginssubstantially after the matrix has degraded sufficiently to uncover thereservoir. Alternatively, methylprednisolone may be disposed in thematrix with the matrix coating a scaffold (FIG. 7). In thisconfiguration, an outer layer of the matrix is substantially free frommethylprednisolone so that methylprednisolone release will notsubstantially begin until the outer layer has degraded. Optionally,methylprednisolone may be disposed within or on a scaffold coated by thematrix (FIGS. 5–6).

The prosthesis 16 may incorporate methylprednisolone 22 by coating,spraying, dipping, deposition, or painting the methylprednisolone on theprosthesis. Usually, the methylprednisolone 22 is dissolved in a solventto make a solution. Suitable solvents include aqueous solvents (e.g.,water with pH buffers, pH adjusters, organic salts, and inorganicsalts), alcohols (e.g., methanol, ethanol, propanol, isopropanol,hexanol, and glycols), nitriles (e.g., acetonitrile, benzonitrile, andbutyronitrile), amides (e.g., formamide and N dimethylformamide),ketones, esters, ethers, DMSO, gases (e.g., CO₂), and the like. Forexample, the prosthesis may be sprayed with or dipped in the solutionand dried so that methylprednisolone crystals are left on a surface ofthe prosthesis. Alternatively, the prosthesis 16 may be coated with thematrix solution by spraying, dipping, deposition, or painting thepolymer solution onto the prosthesis. Usually, the polymer is finelysprayed on the prosthesis while the prosthesis is rotating on a mandrel.A thickness of the matrix coating may be controlled by a time period ofspraying and a speed of rotation of the mandrel. The thickness of thematrix coating is typically in a range from 0.01 micron to 100 microns,preferably in a range from 0.1 micron to 10 microns. Once the prosthesishas been coated with the methylprednisolone/matrix, the stent may beplaced in a vacuum or oven to complete evaporation of the solvent.

For example, a stainless steel Duraflex™ stent, having dimensions of 3.0mm×14 mm is sprayed with a solution of 25 mg/ml methylprednisolone (soldcommercially by SIGMA CHEMICALS) in a 100% ethanol or methanol solvent.The stent is dried and the ethanol is evaporated leaving themethylprednisolone on a stent surface. A 75:25 PLLA/PCL copolymer (soldcommercially by POLYSCIENCES) is prepared in 1,4 Dioxane (soldcommercially by ALDRICH CHEMICALS). The methylprednisolone loaded stentis loaded on a mandrel rotating at 200 rpm and a spray gun (soldcommercially by BINKS MANUFACTURING) dispenses the copolymer solution ina fine spray on to the methylprednisolone loaded stent as it rotates fora 10–30 second period. The stent is then placed in a oven at 25–35° C.up to 24 hours to complete evaporation of the solvent.

In a further embodiment, the means for releasing methylprednisolone maycomprise a reservoir on or within the scaffold holding themethylprednisolone (as shown in FIG. 9) and an external energy sourcefor directing energy at the prosthesis after implantation to effectrelease of the methylprednisolone. A matrix may be formed over thereservoir to contain the methylprednisolone within the reservoir.Alternatively, the means for releasing methylprednisolone may comprise amatrix formed over at least a portion of the scaffold (as shown in FIGS.4–6), wherein the methylprednisolone is disposed under or within thematrix, and an external energy source for directing energy at theprosthesis after implantation to effect release of themethylprednisolone. Suitable external energy source include ultrasound,magnetic resonance imaging, magnetic field, radio frequency, temperaturechange, electromagnetic, x-ray, radiation, heat, gamma, and microwave.

For example, an ultrasound external energy source may be used having afrequency in a range from 20 kHz to 100 MHz, preferably in a range from0.1 MHz to 20 MHz, and an intensity level in a range from 0.05 W/cm² to10 W/cm², preferably in a range from 0.5 W/cm² to 5 W/cm². Theultrasound energy should be directed at the prosthesis 16 from adistance in a range from 1 mm to 30 cm, preferably in a range from 1 cmto 20 cm. The ultrasound may be continuously applied or pulsed, for atime period in a range from 5 sec to 30 minutes, preferably in a rangefrom 1 minute to 15 minutes. The temperature of the delivery prosthesis16 during this period will be in a range from 37° C. to 48° C. Theultrasound may be used to increase a porosity of the prosthesis 16,thereby allowing release of the methylprednisolone 22 from theprosthesis 16.

In yet another embodiment, as depicted in FIG. 10, means for releasingmethylprednisolone comprises magnetic particles 36 coupled to themethylprednisolone 22 and a magnetic source for directing a magneticfield at the prosthesis 16 after implantation to effect release of themethylprednisolone 22. Optionally, the means for releasingmethylprednisolone may comprise magnetic particles 26 coupled to amatrix 20 formed over the scaffold 10 and a magnetic source fordirecting a magnetic field at the prosthesis 16 after implantation toeffect release of the methylprednisolone 22. Methylprednisolone 22 maybe disposed under (FIGS. 5 and 6) or within the matrix 20 (FIG. 10). Themagnetic particles 36 may be formed from magnetic beads and willtypically have a size in a range from 1 nm to 100 nm. The magneticsource exposes the prosthesis 16 to its magnetic field at an intensitytypically in the range from 0.01T to 2T, which will activate themagnetic particles 36, and thereby effect release of themethylprednisolone from the prosthesis.

Referring now to FIG. 11, improved methods for delivering apharmacological agent to an artery are illustrated. The method is of thetype where a prosthesis 16 is implanted in the artery 18 and theprosthesis 16 releases the pharmacological agent 22. The improvementcomprises implanting a prosthesis 16 that is programmed to beginsubstantial release of the pharmacological agent 22 beginning aftergrowth of at least one layer of cells 38 over a part of the prosthesis.The cells 38 will typically comprise inflammation, smooth muscle, orendothelial cells, indicating the onset of restenosis.

Referring now to FIGS. 12A–12C, a method for positioning the deliveryprosthesis 16 in a body lumen in order to deliver methylprednisolone 22therein will be described. As shown in FIG. 12A, a balloon dilationcatheter 70 will typically be used to deliver the prosthesis 16 to aregion of stenosis S in a blood vessel BV. The prosthesis 16 isinitially carried in its radially collapsed diameter configuration on andeflated balloon 72 of the balloon catheter 70. The balloon catheter istypically introduced over a guidewire 74 under fluoroscopic guidance.The catheters and guidewires may be introduced through conventionalaccess sites to the vascular system, such as through the femoral artery,or brachial, subclavian or radial arteries, for access to the coronaryarteries. After the delivery prosthesis 16 is properly positioned withinthe region of stenosis (FIG. 12A), the balloon 72 will be inflated toradially expand the prosthesis 16 (FIG. 12B) within the stenotic region.The balloon 72 may then be deflated, and the catheter 70 may bewithdrawn over the guidewire 74. After removal of the guidewire 74, theexpanded prosthesis 16 will be left in place, as illustrated in FIG.12C, to provide luminal methylprednisolone delivery as described aboveto inhibit restenotic effects.

In general, it will be possible to combine elements of the differingprostheses and treatment methods as described above. For example, aprosthesis having reservoir means for releasing methylprednisolone asillustrated in FIG. 9 may further incorporate a rate limiting barrier asillustrated in FIG. 8. Additionally, methods of the present inventionmay combine balloon angioplasty and/or other interventional treatmentsto resolve a stenotic site with the presently described luminalmethylprednisolone delivery treatments.

The use of methylprednisolone for intravascular delivery is furtherillustrated by the following non-limiting examples.

EXAMPLE 1 Methylprednisolone Loaded on Vascular Stent

A stainless steel Duraflex™ stent, having dimensions of 3.0 mm×14 mm issprayed with a solution of 25 mg/ml methylprednisolone (soldcommercially by SIGMA CHEMICALS) in a 100% ethanol or methanol solvent.The stent is dried and the ethanol is evaporated leaving themethylprednisolone on a stent surface. A 75:25 PLLA/PCL copolymer (soldcommercially by POLYSCIENCES) is prepared in 1,4 Dioxane (soldcommercially by ALDRICH CHEMICALS). The methylprednisolone loaded stentis loaded on a mandrel rotating at 200 rpm and a spray gun (soldcommercially by BINKS MANUFACTURING) dispenses the copolymer solution ina fine spray on to the methylprednisolone loaded stent as it rotates fora 10–30 second period. The stent is then placed in a oven at 25–35° C.up to 24 hours to complete evaporation of the solvent.

EXAMPLE 2 Increased Loading of Methylprednisolone on Vascular Stent

Stainless steel Duraflex stent (3.0×13 mm) is laser cut from a SS tube.The surface area for loading the drug is increased by increasing thesurface roughness of the stent. The surface area and the volume of thestent can be further increased by creating 10 nm wide and 5 nm deepgrooves along the links of the stent strut. The grooves are created inareas which experience low stress during expansion so that the stentradial strength is not compromised. The drug can then be loaded on thestent and in the groove by dipping or spraying the stent inmethylprednisolone solution prepared in low surface tension solvent suchas isopropyl alcohol, ethanol, or methanol. The stent is then dried andthe drug resides on the stent surface and in the grooves, which serve asa drug reservoir. Paralene is then deposited on the stent to serve as arate limiting barrier. The drug elutes from the stent over a period oftime in the range from 1 day to 45 days.

EXAMPLE 3

The methylprednisolone substance is dissolved in methanol, then sprayedon the stent, and left to dry evaporating the solvent with themethylprednisolone remaining on the stent surface. A matrix or barrier(silicone, polytetrafluorethylene, parylast, parylene) is sprayed ordeposited on the stent encapsulating the methylprednisolone. The amountof methylprednisolone varies from 100 micrograms to 2 milligrams, withrelease rates from I day to 45 days.

EXAMPLE 4

A matrix with methylprednisolone coated on a stent, as described inExample 2, and then coated or sprayed with a top coat of a rate limitingbarrier (and/or a matrix without a drug so to act as a rate limitingbarrier). Alternatively, methylprednisolone may be coated on a stent viaa rate limiting barrier, and then covered with a top coat (anotherbarrier or matrix). Use of top coats provide further control of releaserate, improved biocompatibility, and/or resistance to scratching andcracking upon stent delivery or expansion.

EXAMPLE 5

Methylprednisolone may be combined with other drugs (cytotoxix drugs,cytostatic drugs, or psoriasis drugs, such as, mycophenolic acid,riboflavin, tiazofurin, mizoribine, FK 506, zafurin, methotrexate). Forexample, one drug is in or coupled a first coat while methylprednisoloneis in or coupled to a second coat. Methylprednisolone may be releasedfor a longer period than any one of the other above mentioned drugssince methylprednisolone has little impact on endothelialization inhumans, which is needed for complete healing of a vessel.

EXAMPLE 6

A combination of multiple drugs that are individually included indifferent coats. The coats may release the multiple drugs simultaneouslyand/or sequentially. The drugs may be selected from a methylprednisoloneclass of inhibitors of de novo nucleotide synthesis or from classes ofglucocorticosteroids, immunophilin-binding drugs, deoxyspergualin,FTY720, protein drugs, and peptides. This can also apply to anycombination of drugs from the above classes that is coupled to a stentwith the addition of other cytotoxic drugs.

Although certain preferred embodiments and methods have been disclosedherein, it will be apparent from the foregoing disclosure to thoseskilled in the art that variations and modifications of such embodimentsand methods may be made without departing from the true spirit and scopeof the invention. Therefore, the above description should not be takenas limiting the scope of the invention which is defined by the appendedclaims.

1. A method for inhibiting restenosis in a blood vessel followingrecanalization of the blood vessel, said method comprising: implanting avascular prosthesis in the blood vessel; and releasingmethylprednisolone and mycophenolic acid from the prosthesis whenimplanted in the blood vessel.
 2. A method as in claim 1, whereinmethylprednisolone is released from the prosthesis at a rate between 5μg/day to 200 μg/day.
 3. A method as in claim 2, whereinmethylprednisolone is released at a rate between 10 μg/day to 60 μg/day.4. A method as in claim 1, wherein methylprednisolone is released fromthe prosthesis within a time period of 1 day to 45 days in a vascularenvironment.
 5. A method as in claim 4, wherein methylprednisolone isreleased within a time period of 7 days to 21 days in a vascularenvironment.
 6. A method as in claim 1, wherein the releasing comprisesdelaying substantial release of methylprednisolone for at least one hourfollowing implantation of the prosthesis.
 7. A method as in claim 6,wherein delaying release comprises slowing releasing methylprednisolonefrom a reservoir with a material that at least partially degrades in avascular environment over said one hour.
 8. A method as in claim 6,wherein delaying release comprises slowing releasing methylprednisolonewith a matrix that at least partially degrades in a vascular environmentover said one hour.
 9. A method as in claim 6, wherein delaying releasecomprises slowing releasing methylprednisolone with a nondegradablematrix that allows diffusion of methylprednisolone through thenondegradable matrix after said one hour.
 10. A method as in claim 6,wherein delaying release comprises slowing releasing methylprednisolonewith a rate limiting barrier that allows diffusion of methylprednisolonethrough the barrier after said one hour.
 11. A method as in any one ofclaims 8–10, wherein the prosthesis is coated with the matrix or barrierby spraying, dipping, deposition, or painting.
 12. A method as in claim1, wherein methylprednisolone is substantially released within a timeperiod of 2 days to 3 months.
 13. A method as in claim 1, whereinmethylprednisolone and mycophenolic acid are released simultaneously.14. A method as in claim 1, wherein methylprednisolone and mycophenolicacid are released sequentially.
 15. A method for inhibiting restenosisin a blood vessel following recanalization of the blood vessel, saidmethod comprising: implanting a vascular prosthesis in the blood vessel;and releasing methylprednisolone and mizoribine from the prosthesis whenimplanted in the blood vessel.
 16. A method as in claim 15, whereinmethylprednisolone and mizoribine are released simultaneously.
 17. Amethod as in claim 15, wherein methylprednisolone and mizoribine arereleased sequentially.
 18. A method as in claim 15, whereinmethylprednisolone is released from the prosthesis at a rate between 5μg/day to 200 μg/day.
 19. A method as in claim 18, whereinmethylprednisolone is released at a rate between 10 μg/day to 60 μg/day.20. A method as in claim 15, wherein methylprednisolone is released fromthe prosthesis within a time period of 1 day to 45 days in a vascularenvironment.
 21. A method as in claim 20, wherein methylprednisolone isreleased within a time period of 7 days to 21 days in a vascularenvironment.
 22. A method as in claim 15, wherein the releasingcomprises delaying substantial release of methylprednisolone for atleast one hour following implantation of the prosthesis.
 23. A method asin claim 22, wherein delaying release comprises slowing releasingmethylprednisolone from a reservoir with a material that at leastpartially degrades in a vascular environment over said one hour.
 24. Amethod as in claim 22, wherein delaying release comprises slowingreleasing methylprednisolone with a matrix that at least partiallydegrades in a vascular environment over said one hour.
 25. A method asin claim 22, wherein delaying release comprises slowing releasingmethylprednisolone with a nondegradable matrix that allows diffusion ofmethylprednisolone through the nondegradable matrix after said one hour.26. A method as in claim 22, wherein delaying release comprises slowingreleasing methylprednisolone with a rate limiting barrier that allowsdiffusion of methylprednisolone through the barrier after said one hour.27. A method as in any one of claims 24–26, wherein the prosthesis iscoated with the matrix or barrier by spraying, dipping, deposition, orpainting.
 28. A method as in claim 15, wherein methylprednisolone issubstantially released within a time period of 2 days to 3 months.